CN105481924B - A kind of preparation method of progesterone - Google Patents
A kind of preparation method of progesterone Download PDFInfo
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- CN105481924B CN105481924B CN201510821638.6A CN201510821638A CN105481924B CN 105481924 B CN105481924 B CN 105481924B CN 201510821638 A CN201510821638 A CN 201510821638A CN 105481924 B CN105481924 B CN 105481924B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
- C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
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Abstract
The invention discloses a kind of method for preparing progesterone.This method is with compound 3 (2, 2 dimethyl 1, 3 dioxy propyl group) 5 alkene 17 ketone (II) be initiation material, occurs condensation reaction with sulfonvlmethvl isocyanide compound (III) in the presence of alkali, formamido sulfonyl methylene compound (IV) is made, compound (IV) obtains isocyano group sulfonyl methylene compound (V) by dehydration, compound (V) obtains isocyano group sulfonvlmethvl compound (VI) through reduction reaction, compound (VI) obtains isocyano group sulfonyl ethyl compound (VII) through methylation reaction, final compound (VII) obtains target product progesterone (I) through hydrolysis.Integrated artistic of the present invention is easy, and simple to operate, cost is low, suitable for scale production.
Description
Technical field
The present invention relates to the preparation method of organic steroid, more particularly to a kind of preparation method of progesterone.
Background technology
Progesterone (Progesterone), chemical name DELTA4-pregn-3,20-dione, structural formula is as follows：
Progesterone was found in 1933, and success in 1934 is separated from pregnant urine.Progesterone is secreted by corpus luteum
A kind of natural progestogen, has notable Morphology Effects to the endometrium that estrogen was excited in vivo, to maintain gestation must
Need.Progesterone is clinically used for the amenorrhoeas such as threatened abortion, habitual abortion or the reactivity diagnosis of amenorrhoea reason etc..
In addition the precursor of progesterone or cortin, androgen and estrogenic, plays the part of weight in pharmaceutical synthesis field
The role wanted.
Extract that progesterone amount is few and shortcoming of purification difficult out of animal body, progesterone is mainly by chemical synthesis side
Method is obtained.The synthetic route of progesterone mainly has following several：(1) using pregnant steroid -5,16- diene -20- ketone -3- alcohol acetic esters as
Material synthesis (J.Am.Chem.Soc., 1940,62,3349)；(2) synthesized by dehydroepiandrosterone (J.Org.Chem., 1976,
41,1874)；(3) (J.Chem.Soc., 1954,2627) is synthesized by ergosterol, (4) are synthesized by stigmasterol
(J.Am.Chem.Soc., 1950,2617)；(5) it is that raw material is synthesized by cholesterine；(6) chemistry is fully synthetic etc..It is domestic at present
The universal diosgenin (VIII) to be extracted in Chinese yam plant of the industrialized production of progesterone is synthesized for raw material, specific road
Line shows as follows：
But the method that diosgenin (VIII) is extracted from Chinese yam plant has following defect：(1) Chinese yam resource-constrained；
(2) production cycle is long；(3) yield is low；(4) there is production safety hidden danger using substantial amounts of organic solvent and environmental pollution is serious.
In addition, prepare progesterone technique from diosgenin (VIII) there is also many problems in itself.For example, from compound (IX)
Conversion to (X) needs to use toxic heavy metal chromium, produces three wastes pressure；Need to make from the conversion of compound (XI) to (XII)
With there is valuable catalyst palladium, while also needing to control hydrogenation conditions to prevent the carbon-carbon double bond of B- rings to be also reduced.These are all led
Technique productions cost increase is caused, its competitiveness of product in market is reduced.
Van Leusen et al. report the method for synthesizing progesterone for initiation material with compound (XIV)
(Synthesis, 1991,531).The route is that initiation material reacts with TosMIC with diene ether compound (XIV), then through de-
Water, reduce, methylate, hydrolyzing progesterone is made, specific route shows as follows：
There are fatal defects in the route, be exactly it raw material and intermediate it is all unstable, to moisture, acid-sensitive, hold
Facile hydrolysis is into ketenes.For example it is found that compound (XIV) places just Partial Conversion quickly in the drying process, in atmosphere
For 4-AD, 4-AD structural formula is as follows：
The physicochemical property of these diene ether compounds (XIV~XVIII) seriously limits them in industrialized production
Application.In addition, this method uses the iodomethane of costliness as methylating reagent so that this method lacks in auxiliary material cost
Competitiveness.
The content of the invention
The purpose of the present invention is to overcome the deficiencies in the prior art there is provided a kind of method for preparing progesterone.
A kind of method for preparing progesterone provided by the present invention includes：With compound 3- (2,2- dimethyl -1,3- dioxies
Propyl group) -5- alkene -17- ketone (I I) be initiation material, contracted in the presence of alkali with sulfonvlmethvl isocyanide compound (III)
Reaction is closed, formamido sulfonyl methylene compound (IV) is made, compound (IV) is in the presence of dehydrating agent by dehydration
Isocyano group sulfonyl methylene compound (V) is reacted to obtain, compound (V) reduces to obtain isocyano group sulfonyl in the presence of reducing agent
Methyl compound (VI), compound (VI) obtains isocyano group sulfonyl ethyl compound (VII), final compound through methylation reaction
(VII) target product progesterone (I) is obtained through hydrolysis, is expressed as follows with reaction equation：
It is expressed as follows with reaction equation：
Wherein, R is C1-C6 alkyl, C6-C12 aryl.
The reactions steps of the present invention are specific as follows：
(1) 3- (2,2- dimethyl -1,3- dioxies propyl group) -5- alkene -17- ketone (II) in the presence of alkali with sulfonvlmethvl
Isocyanide compound (III) occurs condensation reaction and formamido sulfonyl methylene compound (IV) is made.Compound (I II) with
The mol ratio of compound (II) is preferably 1~1.5:1.Suitable alkali includes lithium alkoxide, sodium alkoxide, potassium alcoholate, such as sodium methoxide, the tert-butyl alcohol
Potassium, tert-butyl alcohol lithium, sodium tert-butoxide, LDA, LHMDS etc., preferably tert-butyl alcohol lithium and potassium tert-butoxide, alkali rub with compound (II's)
That ratio preferably 1~2:1.Solvent is hydro carbons, ethers, such as toluene, ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran.Reaction temperature
For -78 DEG C~0 DEG C.(2) the obtained isocyano group sulfonyl methylenation of dehydration occurs under dehydrating agent effect for compound (IV)
Compound (V).Suitable dehydrating agent includes POCl3, phosphorus trichloride, phosphorus pentachloride, phosphorus pentoxide etc., dehydrating agent and chemical combination
The mol ratio of thing (IV) is 1~20:1.Solvent is ethers and hydro carbons, such as THF, toluene.Reaction temperature is -25 DEG C~25 DEG C.
(3) isocyano group sulfonvlmethvl compound (VI) is made through reduction reaction in compound (V).Suitable reducing agent is selected from
Pd/H2, Ni/H2, sodium borohydride, Lithium Aluminium Hydride, borine etc., solvent is alcohols, esters, ethers, hydro carbons, preferably alcohols and ether
Class, such as methanol, tetrahydrofuran.
(4) isocyano group sulfonyl ethyl is made through methylation reaction under alkali and phase transfer catalyst effect in compound (VI)
Compound (VII).Methylating reagent used in methylation reaction includes halomethane, dimethyl suflfate, Methyl triflate, carbon
Dimethyl phthalate etc., preferably dimethyl suflfate and chloromethanes, the mol ratio of methylating reagent and compound (VI) is preferably 1~
10:1.Suitable alkali is lithium alkoxide, sodium alkoxide, potassium alcoholate, such as sodium methoxide, tert-butyl alcohol lithium, sodium tert-butoxide, potassium tert-butoxide, LDA, LHMDS
Deng.Phase transfer catalyst be selected from crown ether-like, quaternary ammonium salt, such as 18- crown-s 6, TBAB, benzyltriethylammoinium chloride,
The mol ratio of phase transfer catalyst and compound (VI) is preferably 0.01~0.1:1.Solvent is ethers or alkanes, such as tetrahydrochysene furan
Mutter, toluene etc..
(5) progesterone (I) is made through hydrolysis under the action of an acid in compound (VII).Suitable acid for inorganic acid and
Organic acid, such as hydrochloric acid, sulfuric acid, formic acid, acetic acid.Solvent is that the one or more in water, alcohols, ketone, ethers, hydro carbons are mixed
Compound.
The present invention has the advantage that compared with prior art：
1. the method have the characteristics that using the stable raw material being easy to get, involved new intermediate is easier to prepare and managed
Change performance stable.
2. the present invention is using the expensive iodomethane of less expensive methylating reagent fictitious hosts.
3. integrated artistic of the present invention is simple, easy to operate, environment-friendly, cost is low, suitable for scale production.
Embodiment
Following example further illustrate the present invention some features, but the present invention apply protect content with
Scope is not limited by following embodiments.
Embodiment 1：(E) -17- formamidos tolysulfonyl methylene -3- (2,2- dimethyl -1,3- dioxies propyl group)
The preparation 1 of androstane -5- alkene (compound IV)
Under dry ice-propanone bath, THF (40mL), TosMIC (1.95g), compound (II) (3.73g), uncle are sequentially added
Butanol potassium (2.48g), reacts 2h, reaction solution is poured into water, extracted with dichloromethane, and organic layer is concentrated to give 5.4gization through drying
Compound (IV), in weak yellow foam shape solid.
Embodiment 2：(E) -17- formamidos tolysulfonyl methylene -3- (2,2- dimethyl -1,3- dioxies propyl group)
The preparation 2 of androstane -5- alkene (compound IV)
Under dry ice-propanone bath, toluene (50mL), TosMIC (2.93g), compound (II) (3.73g), uncle are sequentially added
Butanol lithium (1.77g), reacts 2h, reaction solution is poured into water, extracted with dichloromethane, and organic layer is concentrated to give 5.3gization through drying
Compound (IV), in weak yellow foam shape solid.
Embodiment 3：(E) -17- isocyano groups tolysulfonyl methylene -3- (2,2- dimethyl -1,3- dioxies propyl group) is male
The preparation 1 of steroid -5- alkene (compound V)
Compound obtained above (IV) (6.38g) is dissolved in tetrahydrofuran (50mL), diisopropyl is added dropwise at -10 DEG C
Amine (4.9mL), is added dropwise POCl3 (1.1mL), reacts 2h.Reaction solution is poured into the 100mL frozen water containing 5g sodium acid carbonates,
Filtering, washing, is dried to obtain 5.9g yellow solid compounds (V).
Embodiment 4：(E) -17- isocyano groups tolysulfonyl methylene -3- (2,2- dimethyl -1,3- dioxies propyl group) is male
The preparation 2 of steroid -5- alkene (compound V)
Compound (IV) (6.38g) is dissolved in toluene (50mL), diisopropylamine (4.9mL) is added dropwise at -5 DEG C, is added dropwise
Phosphorus trichloride (1mL), reacts 3h.Reaction solution is poured into the 100mL frozen water containing 5g sodium acid carbonates, filtered, washing, dry
To 5.8g yellow solid compounds (V).
Embodiment 5：17 β-isocyano group tolysulfonyl ylmethyl -3- (2,2- dimethyl -1,3- dioxies propyl group) androstane -5-
The preparation 1 of alkene (compound VI)
Compound (V) (2.2g) is dissolved in the mixed solution of tetrahydrofuran (20mL) and methanol (20mL), boron hydrogen is added
Change sodium (0.17g), react at room temperature 2h.Solvent is evaporated off in reaction after terminating, add water, extracted with dichloromethane, organic phase is again with 5%
Ammonium chloride solution is washed, and is dried, is concentrated to give 2.1g compounds (VI).
Embodiment 6：17 β-isocyano group tolysulfonyl ylmethyl -3- (2,2- dimethyl -1,3- dioxies propyl group) androstane -5-
The preparation 2 of alkene (compound VI)
Compound (V) (2.2g) is dissolved in methanol (30mL), 0.2g 5%Pd/C is added, is passed through hydrogen, room temperature is anti-
Answer 3h.After reaction terminates, filtering adds water after filtrate is concentrated, extracted with dichloromethane, organic phase is molten with 5% ammonium chloride again
Liquid is washed, and is dried, is concentrated to give 2g compounds (VI).
Embodiment 7：17 β-isocyano group p-toluenesulfonyl ethyl -3- (2,2- dimethyl -1,3- dioxies propyl group) pregnant steroid -5-
The preparation of alkene (compound VII)
By compound (VI) (20.1g), benzyltriethylammoinium chloride (0.9g), dimethyl suflfate (4.6g), 5.5g 30%
Sodium hydroxide solution is added in toluene, 80 DEG C of reaction 2h, is cooled to room temperature, point liquid, organic phase salt water washing, magnesium sulfate is done
Dry, filtering and concentrating obtains white solid 19.5g.
Embodiment 8：The preparation of progesterone (compound I)
Compound (VII) (1.0g) is dissolved in 5mL dichloromethane, 6N HCl are added, flow back 1h, reaction end is cooled to
Washed after room temperature, point liquid with saturated sodium bicarbonate, magnesium sulfate is dried, filtering and concentrating obtains progesterone (I), 0.5g progesterone.
Claims (8)
1. a kind of method for preparing progesterone, it is characterised in that with compound 3- (2,2- dimethyl -1,3- dioxy propyl group) -5-
Alkene -17- ketone (II) is initiation material, occurs condensation reaction, system with sulfonvlmethvl isocyanide compound (III) in the presence of alkali
Formamido sulfonyl methylene compound (IV) is obtained, compound (IV) obtains isocyanide in the presence of dehydrating agent by dehydration
Base sulfonyl methylene compound (V), compound (V) reduces to obtain isocyano group sulfonvlmethvl compound in the presence of reducing agent
(VI), compound (VI) obtains isocyano group sulfonyl ethyl compound (VII) through methylation reaction, and final compound (VII) is through water
Solution reacts to obtain target product progesterone (I), is expressed as follows with reaction equation：
Wherein, R is C1-C6 alkyl, C6-C12 aryl or 4- aminomethyl phenyls.
2. according to the method described in claim 1, it is characterised in that the sulfonvlmethvl isocyanide used in described condensation reaction
Compound (III) is TosMIC reagents, and the mol ratio of compound (III) and compound (II) is 1~1.5:1, described alkali is first
The mol ratio of sodium alkoxide, potassium tert-butoxide, tert-butyl alcohol lithium, sodium tert-butoxide, LDA or LHMDS, alkali and compound (II) is 1~2:1, it is molten
Agent is hydro carbons or ethers, and reaction temperature is -78 DEG C~0 DEG C；Dehydrating agent used in described dehydration is POCl3, trichlorine
The mol ratio of change phosphorus, phosphorus pentachloride or phosphorus pentoxide, dehydrating agent and compound (IV) is 1~20:1, solvent is hydro carbons or ether
Class, reaction temperature is -25 DEG C~25 DEG C；Reducing agent used in described reduction reaction is selected from Pd/H2、Ni/H2, sodium borohydride, four
Hydrogen aluminium lithium or borine, solvent are methanol or tetrahydrofuran.
3. method according to claim 2, it is characterised in that the alkali used in the condensation reaction is tert-butyl alcohol lithium or tertiary fourth
Potassium alcoholate, solvent is toluene, ether, methyl tertiary butyl ether(MTBE) or tetrahydrofuran；Solvent used in described dehydration is THF or first
Benzene.
4. according to the method described in claim 1, it is characterised in that described methylation reaction is made in alkali and phase transfer catalyst
Is carried out with the lower reaction with methylating reagent, methylating reagent used be halomethane, dimethyl suflfate, Methyl triflate or
The mol ratio of dimethyl carbonate, methylating reagent and compound (VI) is 1~10:1, phase transfer catalyst is selected from crown ether-like or season
Ammonium salt class, solvent is ethers or alkanes, and the mol ratio of phase transfer catalyst and compound (VI) is 0.01~0.1:1.
5. method according to claim 4, it is characterised in that the methylating reagent used in described methylation reaction is sulphur
Dimethyl phthalate or chloromethanes, described alkali are sodium methoxide, tert-butyl alcohol lithium, sodium tert-butoxide, potassium tert-butoxide, LDA or LHMDS, and phase turns
Shifting catalyst is 18- crown-s 6, TBAB or benzyltriethylammoinium chloride, and solvent is tetrahydrofuran or toluene.
6. according to the method described in claim 1, it is characterised in that the acid used in described hydrolysis is inorganic acid or organic
Acid, solvent is one or more mixtures of water, alcohols, ketone, ethers or hydro carbons.
7. method according to claim 6, it is characterised in that the inorganic acid used in described hydrolysis is hydrochloric acid or sulphur
Acid, organic acid is formic acid or acetic acid.
8. sulphonyl steroid (IV)-(VII), its structural formula is expressed as follows：
Wherein, R is C1-C6 alkyl, C6-C12 aryl or 4- aminomethyl phenyls.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4647410A (en) * | 1983-04-29 | 1987-03-03 | Gist-Brocades N.V. | Novel 17-substituted steroids |
| EP1149839A1 (en) * | 2000-04-28 | 2001-10-31 | AZIENDE CHIMICHE RIUNITE ANGELINI FRANCESCO A.C.R.A.F. S.p.A. | Progesterone substantially free of delta14-pregnene-3,20-dione |
| CN103524588A (en) * | 2013-11-04 | 2014-01-22 | 浙江神洲药业有限公司 | Method for preparing progesterone |
| CN104098640A (en) * | 2014-08-06 | 2014-10-15 | 赵云现 | Progesterone preparation method |
| CN104945458A (en) * | 2015-06-25 | 2015-09-30 | 湖南科瑞生物科技股份有限公司 | Progesterone synthesis method |
-
2015
- 2015-11-24 CN CN201510821638.6A patent/CN105481924B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4647410A (en) * | 1983-04-29 | 1987-03-03 | Gist-Brocades N.V. | Novel 17-substituted steroids |
| EP1149839A1 (en) * | 2000-04-28 | 2001-10-31 | AZIENDE CHIMICHE RIUNITE ANGELINI FRANCESCO A.C.R.A.F. S.p.A. | Progesterone substantially free of delta14-pregnene-3,20-dione |
| CN103524588A (en) * | 2013-11-04 | 2014-01-22 | 浙江神洲药业有限公司 | Method for preparing progesterone |
| CN104098640A (en) * | 2014-08-06 | 2014-10-15 | 赵云现 | Progesterone preparation method |
| CN104945458A (en) * | 2015-06-25 | 2015-09-30 | 湖南科瑞生物科技股份有限公司 | Progesterone synthesis method |
Non-Patent Citations (3)
| Title |
|---|
| Daan van Leusen et al..A new synthesis of progesterone from 17-[isocyano(tosyl)methylene]-3-methoxyandrosta-3,5-diene.《Synthesis》.1991,(第7期),第531-532页. * |
| Johannes Stoelwinder et al..Chemistry of N,P-acetals: application to the synthesis of 20-ketosteroids.《J. Org. Chem.》.1992,第57卷第2249-2252页. * |
| Synthesis of 17-(isocyanotosylmethylene) steroids: precursors to pregnane derivatives;Daan van Leusen et al.;《Recueil des Travaux Chimiques des Pays-Bas》;19911031;第110卷(第10期);第393-401页 * |
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